12 alpha-halo-3, 11-oxygenated-17alpha-hydroxy-20 oxo steroids of the pregnane series



United States PatentO 12a-HALO-3,1I-OXYGENATED-Ua HYDROXYJlJ OX STEROIDS OF THE PREGNANE SERIES Josef Fried and Josef E. Herz, New Brunswick, NJ fassi'gnors to Olin Mathieson Chemical iCorpnration, New York, N.Y., a corporation of Virginia d N0 Drawing. Filed Apr. 5, '1' 956., S er. 1905576259 a 8 Claims. (Cl. 260-397.45)

This application is a continuation-in-par't of our parent application Serial No. 519,682, filed July 1, T955.

This invention relates to the synthesis of valuable steraids; and it has for its object the provision of (I) an advantageous process of preparing steroids of the re ame (including the allopregnane, pregnene and pregnadiene) series having a 12a-halogen substituent "and fl -kjeto or llfi-hydroxy substituent, and of (TI) certain steroids useful themselves as physiologically ac tive steroids or as intermediates in the preparation of said physiologically active steroids.

the corresponding 'l'2a-h'alo-2l-bromo-allopregnane-11,20-

triol2l-acylefte derivative if a 2l-hydroxy steroid is de- The process of this invention essential-1y comprises: d)

converting a 3;B-acyloxy-l*1)8,1 2i3-epoxy-5a;22 (either "-a or b)-spirostane to the corresponding"ma-halol lfl hydroxy derivatives; (b) oxidizing said derivative to P'the lZa-halo-ll-keto derivative; ('0) "opening the F-ri-ng to produce a 120: halo N "fnrostene 1 1 --one 313,26-dio1 3,26-diacyla'te; (d) opening the Bring to produce a 12 1-halo-allopregnane- 11;20dione 3iS18,i6fl diol3- acylate, 16-(4 methyl-5-acyloxy)pentanoate; (e9 'convert ing said allopregnane to a lZa-halo-aIIopregnane-16a,17aoxido 11,20 dione 3oz ol 3 acylate either directly or through the l2u-halo-A -allopregnene-11,20-dione-3fihol 3-acylate derivative; (f) converting said epoxiderto a;.l2uhal0-16fl-iodo (or bromo) allopregnane 11,20 dione- 3;9,17a-diol 3-acylate derivative; and (g) dehalogenating the latter to the corresponding 12a-halo-a1lopregnane- 11,20-dione-3B, 17oc-di01 i3-acylate derivative.

The resultant 12a halo allopregnane 11,20 dione- 3;8,17a-diol 3-acylate can then be saponifiedfto'lthe corresponding 12a-halo-allopregnane-11;20-dione-3B,17a-diol, which in turn can either be converted to the corresponding 12a-halo-3,20-diketo-l7a-hydroxy-1lfi-hydroxy (or 1l-keto)-steroids of the ,pregnene series (for example: 12a halo A pregnene 17a -01 3,11,20 trione; 12oz halo A pregnene 115,170; diol 3,20 dione;

sired] to the corresponding 12ot-halo-allopregnane-3,11, ZO-iI'iOIlG-l'lu-Ol, and thence to a 20,4oa-dibIOIl1O-l2othalo-allopregnane-l7a-ol-3,11,20-trione by treatment with bromine. The dibromide can then either be converted directly to a 12a halo-n -pregnadiene 17a-ol-3,11,20-trione by means of a tertiary base (e.g., collidine) or to a l2ot-halo-A -pregnene-l7u-ol-3,l1,20-trione via the 20:- iodo 12a halo A pregnene 17a ol 3,11,20 trione intermediate. To convert the resultant ll-keto steroid to the corresponding ll fi-hydroxy derivative, two different series of reactions are possible. First, the 120:- halo-3,l1,20-triketo-17a-hydroxy steroid can be reacted with a semicarbazide to give the ll-keto-3,20-disemicarbazone, thence to the l'l'fl-hydroxy-3,ZG-disemicarbazone by means of an alkali metal boron tetrahydr'ide and finally to the 1l ii hydroxy,z0 diketone by reaction with nitrous acid; or second, the '12u-halo-3J1,20tr-iketo-l'7ahydroxy steroid can be converted to the 3,20-diketal-ilketone derivative, treated with alkali metal boron tetrahydride to form the 3,20-diketal-llfl-hydroxy derivative and then hydrolyzed to yield the 11B-hydroXy-3,20-diketone.

The 3,20-diketal-11B-hydroxy serves the additional function of being an intermediate for the preparation of 12a-ha1o-1lp-hydroxy (or 11-keto) derivatives generally, since this intermediate upon reaction with a base yields the 11B,12;3-epoxide-3,20-diketal which can be hydrolyzed by means of a dilute acid to the ll'B,-l2,8-epoxide-3,20- diketone, which in turn can be treated in the usual manner with a hydrohalic acid to form the 12ot-ha1o-llfl-hydroxy derivative (which can, if desired, be oxidized to the 12ot-halo-11-keto derivative).

The compounds of this invention comprise: (A) 12oz esters thereof with hydrocarbon carboxylic acids having acylate 16-(4-methyl-5-acyloxy)pentanoate; (E) 12cc-hal0 12a halo A pregnadiene 17cc ol 3,11,20 trione;. L and 12a halo A pregnadiene 115,170: diol 3,20

dione) or to the corresponding 12oz halo 3,20 diketo- 17a,21-dihydroxy-1lB-hydroxy (or l.l-keto,)-stertoids of the pregnene series or 2l-esters thereof Te.g., l2a-halo- A -pregnene-l7a,21-dio1-3,l1,20-trione and esters thereof (particularly esters with hydrocarbon carboxylic acids of less than ten carbon atoms as exemplified by acetic and benzoic acid esters), l2a-halo-A -pregnene-11p,l7a,21- triol-3,20-dione and 21-esters thereof, 12a-halo-A -pregnadiene-17a,21-diol-3,11,20-trione and esters thereof, and

12a halo A pregnadiene llp,l7a,2l triol 3,20- This series of conversions is dione and esters thereof]. 7 effected by oxidizing the l2a-halo-allopregnane-l1,20- di0ne-3fi,17a-diol [after treatment with bromine to form (preferably chloro or fluoro)-A -allonre;znane-3B-0l-11, :zonmmawne; (F) l2u-halo (preferably chloro or fluoro) allopregnane l6a,l7oc oxido 3B o1 11,20- dione 3-acylate; (G) 'IZa-halo (preferably chloro or fluor0)-16;3-bromo (or iodo)allopregnane-35,l7a-diol- 11,20-dione 3-acylate; (H) 12u-halo steroids of the genm1 formula wherein the 1,2 and 4,5 positions are either saturated or double-bonded, R is hydrogen, R is hydroxy or acyloxy (preferably an ester of a hydrocarbon carboxylic acid having less than ten carbon atoms), or together R and R is keto, ketal (preferably either a ketal of a lower alkanol or a lower alkanediol), or semicarbazone [it being understood that if R and R is ketal, the double bond, if any, in the 4,5-position shifts to the 5,6-position], R" is hydrogen, R' is B-hydroxy, or together R" and R' is keto; X is a-halo; Y is hydrogen, bromine, hydroxy or acyloxy (preferably an ester of a hydrocarbon carboxylic acid having less than ten carbon atoms), andZ is keto, ketal (preferably either a ketal of a lower alkanol or a lower alkanediol) or semicarbazone; (I) 2a,4a-dibr0m0- 12a-halo steroids of the general formula CHzY wherein X is a-halo (preferably chloro or fluoro) and Y is hydrogen, hydroxy or acyloxy (preferably an ester of a hydrocarbon carboxylic acid having less than ten carbon atoms); (J) Za-iOdO-IZa-hfllt) steroids of the general formula I I Br wherein X and Y are as hereinbefore defined; and (K) 11,8,l2fi-epoxy steroids of the general formula CHIYI wherein the 1,2 and 4,5-positions are either saturated or double-bonded (preferably the 1,2-position is saturated and the 4,5-position is double-bonded), and Z is keto 0r ketal (preferably either a ketal of a lower alkanol or a lower alkanediol) [it being understood that if R and R' is ketal, the double bond, if any, in the 4,5-position shifts to the 5,6-position], and Y' is as hereinbefore defined.

The final products of this invention [Compounds H, wherein the 4,5-position is double-bonded and Z and R-l-R' are keto] are physiologically active steroids which possess glucocorticoid as well as mineralocorticoid activity. Thus, these new steroids of this invention can be administered instead of, and in the same manner as, cortisone or hydrocortisone in the treatment of rheumatoid arthritis and dermatomyositis, or in the same manner as desoxycorticosterone in the treatment of Addisons disease or adrenal insufiiciencies. The dosage for such administration is, of course, dependent on the relative activity of the compound. The 12a-bromo-11- keto-steroids are of further use as intermediates in the preparation of the corresponding 12-debromo derivatives, to which they are converted by treatment with either zinc dust in acetic acid or chromous chloride.

For a clearer understanding of the foregoing general and following detailed description of the processes of this invention, reference is made to the following schematic analysis, wherein the capital letters designate the general class of compounds and the Roman numerals the specific embodiments thereof of the examples:

' no HX -0 Compounds H containing oxo radicals in the 3- and ll-positions can then be converted to the corresponding llfl-hydroxy derivatives or to an ll-keto or 1113- hydroxy derivative having a different halogen substituent in the lZm-posjtion by the following series of steps:

XLIV X=Cl; Y=0H (1,2-saturated; 4,5-double bonded) XLV X=Gl; Y=OH;

Z"=-0 011,011,0- (1,2-saturated; 5,6-double-bonded) Compounds A are then oxidized, as by treatment with chromic oxide, to the corresponding l2a-halo ll-keto-3fiacyloxy-5a-spirostane derivative, Compounds B [e.g., 12oz chloro 5a,22a spirostane 3B o1 11 one 3-acetate, Compound III, and 12a-fiuoro5a,22a-spiro- XLIX X=Cl; Y=0H (1,2-saturated; 4,5 double-bonded) L X-B 00 r, a (1,2-saturated; 4,5-donble bonded) (1,2-saturated; 4,5-double-bonded) XLV CH III Y- 3000 (1,2-saturated; 4,5-double-bonded) To prepare the steroids of this invention, SB-acyloxy- 11p,12B-epoxy-5a-spirostane (e.g., 3B-acetoxy-11fl,l2flepoxy-Sa,22a-spirostane) is treated with a hydrohalic acid (preferably either hydrochloric or hydrofluoric acid) in the usual manner to yield the corresponding 12ahalo (preferably chloro or fluoro)-11;8-hydroxy-3fl-acyloxy-5a-spirostane, Compounds A, [e.g., l2a-chloro-5a, 22a-spirostane-3fi,llfi-diol 3-acetate, Compound I, and 12a-fluoro-5a,22a-spirostane-3p,1IB-diol 3-acetate, Compound II]. The esterifying radical in the 3-position will depend, of course, on the particular ester derivative of the epoxyspirostane initially chosen, and since the sole function of this ester group is to protect the 3p-hydroxyl radical, any acid is utilizable. Because, of their availability, however, the preferred acids are those of hydrocarbon carboxylic acids containing less than ten carbon atoms and include the lower alkanoic acids (e.g., acetic, propionic, and enanthic acids), the aromatic acids (e.g., benzoic, toluic and xyloic acids), the cycloalkanoic acids (e.g., cyclohexanecarboxylic acid), and the aralkanoic acids (e.g., phenylacetic and phenylpropionic acid).

stane-3fl-ol-11-one 3-acetate, Compound IV]. This reaction is preferably conducted in an inert organic solvent (e. g., acetone).

Compounds, B are then heated under substantially anhydrous conditions, preferably in an organic solvent comprising an acid anhydride and a Lewis acid, e.g., pyridine hydrochloride, to open the F ring, thereby yielding the corresponding 12a-halo-11-keto-3fl-acyloxy-A -furostene-26-0l 26-acylate derivative, Compounds C, wherein the 26-acyl radical corresponds to the acyl radical of the acid anhydride employed in the reaction. Examples of such furostene derivatives include 12a-chloro-A -furostene-3fl,26-diol-11-one 3,26-diacetate, Compound V, and 12a-fiuoro-A -furostene-3 3,26-diol-1l-one 3,26-diacetate, Compound VI. The reaction is preferably effected by refluxing the spirostane and pyridine hydrochloride in acetic anhydride under anhydrous conditions.

Compounds C are then oxidized either by means of a peracid (e.g., peracetic acid formed in situ by means of acetic acid and hydrogen peroxide) or chromic acid to yield the corresponding 12a-halo-11-keto-3fl-acy1oxyi9 allopregnane 16B :olV-. 2'0tone 16 (4 methyl ,acyloxy)pentanoate, Compounds -.D ,[e.g,, 1 2achloro- 'alIQpregnane-SB,lofi-diol-l1,20-dione Ii-acetate, 16-(4- methyl-S-acetoxy)pentanoate, Compound VII, and 120:- ifluoro-allopregnane-3 3,l6,B-diol-l1,20-dione S-acetate, 1,6-

(4-methyl-5-acetoxy)-pentanoate, Compound VIII].

:Compounds D can' then either be dehydrated by treatment with a base (e.g., potassium hydroxide) to the Icorresponding 12a-halo-1 1-keto-3fl-acyloxy-A -allopreg- :nene-IZO-one, Compounds (e.g., 12-a-ch1oro-A -allopregnene-3fl-ol-Ll,20-dione 3-acetate, Compound -IX, or ll2wffiuoro-A -allopregnene-3p8-ol-11,2'0-di0ne 3-ace'tate, Compound X), and thence by treatment of the "resultant Compounds E with hydrogen peroxide and an alkali hydroxide or carbonate to the corresponding -12oc-h al0- Ll :ket'o -33 acyloxy allopregnane '1-6c ,l7a oxido- ZO-o'ne, Compounds F (erg, 1-2a chloro allopregnane- 16a,lh-oxido-ZB-ol-l1,20-dione 3-acetate, -Comp'ound XI, or 1Zea-fluormallopregnane1 6a,l7u-oxido 3p ol lL 20-di0ne 3-acetate, Compound .XII) or directly to Compounds F by treatmentlof Compounds D with hydrogen peroxidein .a :basic medium (e,'g.," 'methanolic sodium hydroxide).

Compounds F are then hydrohalogenated by treatment with either hydrobromic or hydroiodic acid to yield the corresponding 12a-halo-l6 3-bromo (or iodo)-ll-keto- 3B-acyloxy-allopregnane-17a ol-20-one derivatives, Compounds G (e.g., '1'2u-ch1oro-1-6B-bromo-allopregnane-318, 17m-diol-11,20-dione '3-acetate, Compound XIII, 12achloro 16p iodo .all'opregnane 33,170; diol ll, 2-0-dione 3-acetate, Compound XIV, and IZm-fiHOrO-lfifiiodo allopregnane 35,170 diol 11,20 dione 3- acetate, Compound XV).

Compounds G are then dehalogenated in the l6-position by treatment with a reducing agent such as Raney nickel or palladium and hydrogen to yield the corresponding 12a-halo-11-keto-3fieacyloxy-allopregnane l7aol-20-one derivatives, Compounds Ha (e.g., l2tx-chloroallopregnane-BB,17u-diol-l1,20-dione 3-acetate, 1Compound XVI, and 12a-fluoro-all0pregnane-3B,l7a-diol-l1, 20-dione, Compound XVII).

Compounds 'Ha can then be saponified by treatment with an acid (e.g., perchloric acid) or base (e.g., potassium carbonate) in a lower alcohol to yield the corresponding 12u-halo-allopregnane-3 3,17a-dio1-11,20-dione, Compounds Hb (e.g., l2m-chloro-allopregnane 3fl,17adiol-11,20-dione, Compound XVIII, and 12a-fluoro-allopregnane-3,8,17a-diol--l1,20-dione, Compound XIX).

If a 21-hydroxy steroid is desired, Compounds Hb are then brominated in the 21-position by treatment With bromine in an inert organic solvent to yield the corre sponding 12oz halo --21 bromo allopregnane 313,170;- diol-ll,20-dione, Compounds Ho (e.g., 12a-chloro-2'lbromo-allopregnane-3B,l7ot-diol-11,20-dione, Compound XX, and 12a-fluoro-21-bromo-allop1'egnane-3p,17a-diol- 11,20-dione, Compound XXI) in which the 21-bromine atom is then replaced by an acyloxy group by means of an alkali salt of an organic acid, preferably acetic acid, whereby the resultant 21,-substituent ;is an ester "of the acid employed, to yield the corresponding 12a-halo- 21 a-cyloxy allopregnane 35,17a diol 11,20 dione, Compounds Hd (e.g., 12u-chloro-allopregnane-3,3,17a, 2l-triol-ll,20-dione 2l-acetate, Compound XXI I, and 12a 'fluoro allopregnane 3/3,17a,21 triol 11,20- dione ZI-acetate, Compound XXIII), which may'then be hydrolized, if desired, to yield theiree 2l-hydroxyl derivatives.

Compounds Hd or Compounds Hb (if a 2l-unsubstituted steroid is desired) are then oxidized by treatment with chromic acid to yield the corresponding l2a-halo- 3,11 diketoallopregnane, Compounds He e.g. 12achloro allopregnane 1711,21- diol 3,11,20 trione Zl-acetate, Compound XXIV, l-2a-fluoro-allopre gnane- 17a,2l-diol-3,l1,20-trione Zl-acetate, Compound XXV, 12a chloro allopregnane 9 17a ol 3,11,20 trione,

dibromo allopregnane l7w- 01 3,11,20 trione, Co'mpound XXXI) To prepare the corresponding u -jpregnene, Compounds I are heated with an iodide salt (e.g., sodium iodide) whereby the corresponding 12a halo 2a-iodo-A pregnene derivative, Compounds J, are formed (e.g., IZa-chloro- -2w-iodo-cortisone 2l-acetate, Compound XXXII, 12afluoro-2a-iodo-cortisone' 2:1-acetate, Compound XXXIII,

12cc chloro 2a --iodo '11 keto 17a hydroxyprogesterone, Compound XXXIV, fand l2oc-fluoro-2a-iodoll-keto-l7a-hydroxyprogesterone, Compound XXXV),

and the iodo radical is removed by reaction with areducing agent such as aqueous chromous chloride to yield Compounds Hf (e.g., 12a-chloro-cortisone 2l-acetate,

Compound XXXVI, 12u-fluoro-cortisone ZI-acetate, Compound XXXVII, 12x-chloro-1l-keto-17ot-hydroxyprogesterone, Compound XXXVHI, and 12a-fiuoro-1l-keto l'la-hydroxyprogesterone, Compound XXXIX).

To obtain a A -pregnadiene derivative, Compounds I are heated with collidine to yield the corresponding A -pregnadiene derivative, Compounds Hg (e.g., 12achloro A pregnadiene -17a,2l diol 3,11,20 t-rione 2 1-acetate, Compound XL, l2a-fiuoro-A -pregnadienel7u,2l diol-3,11,20-trione 21-acetate, Compound XLI,

12oz chloro A pregnadiene 170a o1 3,1 1,20- trione, Compound XLII, and lZu-fluoro-A -pregnadienel7aeol-3,11,20-trione, Compound XLIII).

Compounds Hf and Hg, containing a 21-acyloxy radical can be hydrolyzed in the usual manner, as by the use of a salt of a strong base and a weak acid (e.g.,

potassium carbonate) to yield the free Zl-hydroxyl derivative (e.g., l2u-chlorocortisone, IZa fluorocortisone,

12cc chloro A --pregnadiene 17a,21 diol 3,11,20- trione and l2a-fluoroA -pregnadiene-l7u,2l-diol 3,l1, 20-trione).

Compounds He, Hf, and Hg can further be converted to the corresponding llfl-hydroxy derivatives by either of two processes. In the first process, the steroid is treated with semicarbazide in a lower alcohol to yield the 3,20-disemicarbazone, Compounds Hh, which are then treated with an alkali metal boron or lithium tetrahydride (e.g., potassium boron tetrahydride) in an organic solvent inert towards the tetrahydride (either in the presence or absence of water) to yield the corresponding llB-hydroxy derivative, Compounds Hi, and the resultant steroids are then reacted with nitrous acid in a dilute mineral acid (e.g., hydrochloric acid) to yield Compounds H, having an llp-hydroxy radical, the halo radical of the starting steroid and keto groups in the 3,20-positions (e.g., 12a-chlorohydrocortisone, 12ccfluorohydrocortisone, 12a chloro 1113,17a dihydroxyprogesterone, 12oz fluoro 115,170: dihydroxy progesterone, 12oz chloro A pregnadiene 1118,1711, 21-triol 3,20 dione, 12a fluoro A pregnadienellfl,l7a,2l triol 3,20 dione, 12cc chloro A pregnadiene 115,170: diol 3,20 dione, 12oz fiuoro- A pregnadiene 1113,17a diol 3,20 dione, 12achloro allopregnane 11/3,17oc,21 triol 3,20 dione, 12a chloro allopregnane 11/3,17a,21 triol 3,20- dione, l2a-chloro-allopregnane-1lfl,l7u-diol-3,20-dione and l2a-fluoro-allopregnane-l 113,17a-di0l-3 ,20-dione) In the second process, Compounds Hf or Hg are first hydrolyzed and then ketalized by treatment with a 1,2-

presence of an acid catalyst, to form the corresponding 3,20-diketal derivatives, Compounds Hj, which are then reduced with an alkali metal boron or lithium tetrahydride, as described hereinbefore, to yield the l15-hydroxy 3,20-diketal derivative, Compounds Hk. The latter are then either treated with a dilute acid, such as sulfuric acid in methanol, to yield a 12a-halo-115-hydroxy-3,20-

'diketo steroid wherein the halo group is that of the starting steroid, or dehydrochlorinated (when the 120:- halo substituent is chlorine) to the corresponding 115, 125- epoxide, Compounds Ka, by treatment with a salt of a strong base and a weak acid (e.g., potassium carbonate). The resultant epoxide ketalized in the 3,20- positions, is then hydrolyzed with diluted acid (e.g., sulfuric acid) to yield the corresponding 115,125-epoxy- 3,20-diketo derivative, Compounds Kb, which can then be treated with a hydrohalic acid (e.g., hydrofluoric, hydrochloric, hydrobromic, or hydroiodic acid), preferably after esterifying any free 21-hydroxyl radical present, to yield the respective 12a-halo-1l5-hydroxy derivative. The resultant 12u-halo-115-hydroxy steroid, can,

if desired, be oxidized with chromic acid to its 12a-haloll-keto derivative, thereby affording a generalized method for producing any 12och3l0-11-k6t0 derivative.

The following examples are illustrative of the invention (all temperatures being in centigrade):

EXAMPLE 1 911- uoro-5or,22a-spir0stane-35,125-di0l 3-acetate Into a solution of 2 g. of 1l5,125-epoxy-5a,22a-spirostane-35-ol 3-acetate in 76 ml. of chloroform and 4 ml. of absolute alcohol is passed with stirring at a stream of hydrogen fluoride. After 10 minutes two layers form and the addition of hydrogen fluoride is terminated. After 75 minutes at 0, the reaction mixture is neutralized with a suspension of sodium bicarbonate in water and the layers separated. The chloroform is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The crystalline residue upon one crystallization from chloroform-alcohol furnishes pure 9m fluoro 5a,22a-spirostane 35,125 diol 3 acetate having the following properties: M.P. about 251-252";

[111 70 (c. 0.96 in chloroform) mg 2.69 ,u, 5.76 pl Analysis.-Calc. for C H O F (492.65): C, 70.69; H, 9.21; F, 3.85. Found: C, 70.66; H, 9.02; F, 3.91.

The 125-acetate of 9a-fluoro-5a,22a-spirostane-35,125- diol 3-acetate can be prepared by allowing a solution of 25 mg. of the compound in 0.5 ml. of pyridine and 0.5 ml. of acetic anhydride to remain at room temperature for 18 hours, and removing the reagents to yield a crystalline residue consisting of the 125-acetate, which after recrystallization from 95% ethanol has the following properties: M.P. about 257-258"; [M 75 (c. 0.98 in chloroform);

Analysis.Calc. for C H O F (534.66): C, 69.64; H, 8.86. Found: C, 69.76; H, 8.61.

The mother liquors of the above reaction with hydrogen fluoride are combined and dissolved in 10 ml. of benzene and 20 ml. of hexane. After centrifuging off a small flocculent precipitate, the resulting solution is chromatographed on g. of sulfuric acid-washed alumina. Elution of the column with 700 ml. of a mixture of one part of benzene and two parts of hexane furnishes after recrystallization from 95 ethanol, pure lZea-fluoro-5a,22a-spirostane-35,1l5-diol 3-acetate having the following properties: M.P. about 239-241"; [(11 44" (c. 0.65 in chloroform);

mm 2.86 ,u. 5.82 5 Analysis.Calc. for C H O F (492.65): C, 70.69;

Found; C, 70.67; H, 9.11.

' 12 EXAMPLE 2 A solution of 3.43 g. of 35-acetoxy-12u-chloro-5a,22aspirostane-115-ol (II) (see J. Schmidlin and A. Wettstein, Helv. 36, 1241 (1953) in 340 ml. of reagent grade acetone is oxidized dropwise, with stirring at room temperature with 4.1 ml. of CrO solution (excess, calc. amount 2.4 ml. solution containing 200 mg. CrO and 320 mg. conc. H 50 in 1 ml. water). The excess CrO is destroyed by addition of 1 ml. of ethanol and after addition of 100 ml. of water, the solution is decanted from remaining salts, concentrated in vacuo until most of the acetone is removed and the resulting crystals filtered off. Yield about 2.87 g. (84%), M.P. about 173-176". The analytical sample is recrystallized several times from ethanol and has the following properties: M.P. about 183-185", [11],; (c. 0.44 in chloroform),

5.76 5., 5.78 5 (doublet), 5.85 p.

Analysis.-Calcd. for C H., O Cl (505.08): C, 68.96; H, 8.18; Cl, 7.02. Found: C, 68.49; H, 8.20; Cl, 6.18.

EXAMPLE 3 12u-fluoro-5a,22a-spir0stane-35-ol-1I-one 3-acetate (IV) Rernoval of the .solvent from the sodium sulfate-dried extract furnishes the crude ll-ketone, which after crystallization from alcohol has the following properties: M.P. about 203-204"; [M 6" (c. 1.28 in CHCl 8x21? 5.79 5, 5.82 (shoulder) Analysis.Calcd. for C H O F (490.63): C, 70.99; H, 8.83. Found: C, 71.13; H, 8.66.

EXAMPLE 4 12a-chlor0-A -fur0stene-35,26-diol-I 1 one 3,26 diacetate (V) A solution of 4.45 g. of the 12a-chloro-1l-ketospirostane (III) prepared in Example 2 and 2 g. of pyridine hydrochloride in 23 ml. of acetic anhydride is refluxed under exclusion of moisture for 5 hours. The mixture is then cooled in an icebath and the acetic anhydride destroyed by careful addition of ice. The mixture is extracted with ethyl acetate, the ethyl acetate extract washed free of acetic acid and pyridine, dried over sodium sulfate and evaporated in vacuo. A yield of about 4.84 g. of the crude furostene diacetate (V) is obtained. Several recrystallizations from ethyl acetate yield the analytical sample, M.P. about 118-119"; lul +7 (c. 0.4 in chloroform);

max.

EXAMPLE 5 12oz chloro allopregnane 35,165 diol 11,20 dione 3-acetate, 16-(4-methyl-5-acet0xy)pentan0ate (VII) *(a) Oxdidation with peracetic acid. A solution of 4.02

g. of the crude, noncrystalline furostene diacetate (V) m 52.5 ml. of glacial acetic acid and 31.5 ml. of 30% :H O is allowed to :stand 31131 001121 temperature for hours. .6 m1. of water is then added dropwise with stlrring and the crystals filtered Off, washed with 50% .acetic acid and water. About 1.93 g. of VIIis obtained "(M.P. .about 190-195") which after 'recrystallizationifrom acetone-hexane has the following properties: M.P. about 191-193"; [M -31 .(c. 0.45 ,in chloroform);

Analysis.-.'Calcd. for C H O 'Cl (581.13): C, 63192; H, 7.81. Found: C, 63.56; H, 7.57.

(b) By oxidation with chromic acid: To a solution of 100 mg. of the spirostane diacetate (V) in amixture of 2 ml. of ethylene dichloride, 2ml. of glacial acetic acid and 0.4 ml. of water is added with stirring at over a 30-minute period 2 ml. of a solution of chromic acid in acetic acid mg./ml.). The. reaction mixture is allowed to warm up to and remain atroom temperature for an additional two hours. Excess chromium trioxide is destroyed by the addition of 0.5 ml. of alcohol and the .furostene, 12a-fluoro-allopregnane-3B,16fi-diol- 11,20 dione 3-acetate-l6-(4-methyl-5-acetoxy)pentanoate (VIII) is formed.

EXAMPLE 6 To a solution of the allopregnane derivative (VII) in 4 ml. of tertiary butanol is added a solution of ,200 mg. of KOH in 0.3 ml. of water. The mixture is allowed to remain at room temperature for.l.5 hours and then neu tralized with dilute hydrochloric acid. Water is added and the mixture extracted with ether. The ether extract is dried over sodium sulfate and the solvent removed in vacuo. The residue is reacetylated with 1 ml. of .pyridine and 1 ml. acetic anhydride for 18 hours and after removal of the reagents in vacuo dissolved in 5 ml. of benzene and 5 m1. of'hexane'for chromatography on 3 g. of sulfuricacid washed alumina. Elution of the columnwith benzene-hexane 1:1 furnishes in the first 200 ml. the desired A eallopregnene derivative (IX), which after crystallization from etherhexane has the following properties: M.P. about 202-204; [a] +3 (c. 0.32 in chloroform) 229 ($11,000), was 5.76 t, 5.85 6.03 t,

max.

Analysis.-Calcd. for C H O Cl.(406.94): C, 67.88; ,H, 7.68. Found: C, 67.77; H, 7.60.

In the same manner, by substituting 12u-fluoro-allopregnane-35, 1 6,8-diol-1 1,20-dione 3-acetate-16-(4-methyl- S-acetoxy) pentanoate (VIII) for the chloro compound in the procedure of Example 6, 12u-fluoro-A -allopregnene-3fl-o1-1L20-dione 3-acetate (X) 'is formed.

EXAMPLE 7 lZu-chloro-allopregnaneJ6oi,1 7 a-oxido-Sfl-ol-I 1 ,20-dione 3-acetate (XI) To a solution of 100 mg. of l2u-chloro-A -allopregnene-3B-ol-l1,20-dione 3-acetate (IX) in 8 ml. of cold methanol, 0.9 ml. of cold H 0 and 0.37 ml. of 4 N NaOH is added. The mixture is allowed to remain at 0 for 6 hours and then diluted with water and neutralized with dilute hydrochloric acid. Chloroform is added and the resulting chloroform extract is washed with water, dried over sodium sulfate and evaporated to dryness in acetic .anhydride and ,1 ml. of pyridine :for s15 rhours and diluteiacetic acid and water until neutral. sepoxide :(XI) melts at about 272-275 (yield approximnately 1847 mg.). tchloroform, the chloroform extract washed free of "hy- .drogen peroxide and acetic acid with sodium bicarbonate solutionvand water, dried over sodium sulfate and evap- EXAMPLE 8 1.93 g. ofVII is suspended in 157 ml. of cold methanol and 17.3 ml. of cold 30% H 0 and 7.8 ml. of cold 4 N :NaOH are added. The mixture is stirred-with cooling in an :icebath .for 6 hours, then about ml. water is slowly added and=the mixture filtered quickly, and washed The crude :The mother liquor is extracted with orated ;to dryness in vacuo. The residue after reacetylation.with :2.ml. of pyridine and 2 ml. of acetic anhydride furnishes ;an additional 330 mg. of XI after crystallization of the crude .acetylation residue from ethanol.

The analytical sample obtained by recrystallization from 95% alcohol has the following properties: M.P. about278.80, [d] -.-6 (c. 0.21 in chloroform),

A232 5: n, M

Analysis-Calcd. for C H O Cl (422.94): C, 6531;

5H, 7.39. Found: C, 65.30; H, 7.44.

EXAMPLE 9 Dot-chlaro-Ilifl-bromo-allopregnane S 8,1 7a-di0l- 11,20-di0ne 3-acetate (XIII) To a solution of90 mg. of the 16x,17ot-epoxide (XI) in 3 ml. of glacial acetic acid is added 1 ml. of 7% HBr in, ace,tic acid .,(1 part of 48% aqueous HBr plus 6 parts 7 of glacial-acetic acid. The reaction mixture is allowed to stand at room temperature over night, poured on ice and extracted with chloroform. The chloroform extract .is washedwith water, sodium bicarbonate and again with water, dried oversodium sulfate and evaporated to dryness in vacuo. The residue (about 103 mg.) after recrystallization from acetone-hexane furnishes the pure .bromohydrin of the following properties: M.P. about 219-220, .[oz] -37 (c, 0.4 in chloroform);

Analysis.-Calcd. for C H O ClBr (503.87): C, 54.82; 16.40. Found: c, 54.22; H, 6.27.

EXAMPLE 1O form. The chloroform extract is washed with water,

sOdiumb-iearbonate solution and again with water containing a small amount of sodium sulfite. The chloroform solution is dried over sodium sulfate and evaporated to. dryness in vacuo. The residue (about 547 mg.) crystallizes readily from alcohol and is used in the next step without further purification. An analytical yaegq. Theresulting residue is acetylated with 1 ml of ,75 after recrystallization from alcohol has the fol- 15 lowing properties: M.P. about 188-190 (dec.), lIot'J -14 (c. 0.66 in chloroform);

P 2.75 p, 5.78 n, 5.85 p

IZa-ChIr0-all0pregnane-3fiJ 7ot-diol11,20-dione 3-acetate (XVI) To a solution of 1.0 g. of the 12a-chloro-16B-iodide (XIV) in 50 ml. of peroxide free dioxane is added 8 ml. of neutral Raney nickel (commercial, pyrophoric) suspended in 10 ml. of dioxane and the resulting suspension shaken in the dark at room temperature for 1 hour. The catalyst is centrifuged off and the solution is diluted with water and chloroform. The chloroform-dioxane phase is separated off, dried over sodium sulfate and the solvents evaporated in vacuo. The crystalline residue after recrystallization from 95% alcohol furnishes pure 12u-chloroallopregnane-3B,17a-diol-11,20-dione 3- acetate of the following properties: M.P. about 222-224"; (a] 35 (c. 0.42 in chloroform);

Nuiol m 2.87 1, 5.79 p, 5.82 M (shoulder), 5.87 p.

Analysis.Calcd. for C H O Cl (424.96): C, 65.16; H, 7.83. Found: C, 64.71; H, 7.44.

Similarly, by substituting 12a-fiu'oro-l6,3-iodoallopregnane 3fi,17a-diol-11,20-dione 3-acetate (XV) or 120:-

EXAMPLE 12 1 2oc-chloro-allopregnane-' 8,1 7u-diol-1 1 ,ZO-dione (XVIII) A solution of 610 mg. of 12ot-chloroallopregnane-3B, 17cz-diOl-1l,20-d10lle 3-acetate (XVI) in 60 ml. of methanol and 0.6 ml. of 70% perchloric acid is refluxed for 2 hours. The solution is then neutralized with sodium bicarbonate solution, diluted with water and the methanol removed in vacuo. Chloroform is added and the resulting extract washed with bicarbonate solution and with water. The dried extract after evaporation of the solvent in vacuo furnishes 12a-chloroallopregnane-3B,l7a-diol- 11,20-dione (XVIII), which after recrystallization from 95% alcohol has the following properties: M.P. about 221-222, [(11 34;

A222 2.96 3.05 u (shoulder), 5.82 5.92 p

EXAMPLE 13 12u-chlore-21-bromo-allopregnane-3/8,1 7u-di0l-1L20- dione (XX) To a solution of 150 mg. of 12ot-chloroallopregnane- 3B,17a-diol-11,20-dione (XVIII) in 9 ml. of chloroform is added at room temperature with stirring 1.60 ml. of a solution of bromine in chloroform (43.2 mg./ml.).

To initiate the reaction a drop of 10% HBr in acetic acid is added. A total reaction time of 8 minutes is re- 7 quired. At the end of that period water is added and the chloroform solution washed neutral with sodium bicarbonate. After drying over sodium sulfate the solvent is removed in vacuo and the residual bromo compound crystallized from acetone-hexane. Pure 12oc-Chl0IO-21- 'bromoallopregnane-3[3,17a-di0l-11,20-dione has the following properties: M.P. about 195-196 (dec.); [111 37 (0. 0.68 in CHCI Nuinl mm 2.85 p, 3.06 u, 5.83 p Analysis.-Calcd. for C H O ClBr (461.81): C,

' 54.61; H, 6.54. Found: C, 55.68; H, 6.72.

Similarly 12a. fiuoro allopregnane 35,170 diol- 11,20-dione can be brominated to 12a-fiuoro-2l-bromoallopregnane-3p,17a-diol-11,20-dione (XXI).

EXAMPLE 14 1 Zea-Ch l0ro-all0pregnane-3 8,1 70:,21 -tri0l-1 1,20-dione 2I-acetate (XXII) with stirring for 17 hours, after which period water is added and the acetone removed in vacuo. Ethyl acetate is then added to the aqueous suspension and the layers separated and the ethyl acetate solution washed with sodium bicarbonate and with water. The sodium sulfate-dried ethyl acetate extract is concentrated to dryness in vacuo and the resulting crystalline residue recrystallized from 95% alcohol. The pure compound has the following properties: M.P. about 158-160"; [111 -17 (c. 0.75 in CHCl m 2.85 3.00 5.75 t. (shoulder), 5.82

Analysis.Calcd. for C H O Cl (440.94): C. 62.64; H, 7.54. Found: C, 62.45, H, 8.02.

Similarly 12m fluoro 21 bromo allopregnane- 3p,17a-diol-11,20-dione yields IZa-fiuoro-allopregnane- 3B,17ot,2l-triol-11,20-dione 2l-acetate (XXIII).

EXAMPLE 15 120: chloro allopregnane-I70;,2]-di0l-3,11,20-tri0ne 21- acetate (XXIV) added. After removal of the acetone in vacuo chloroform is added, the resulting chloroform extract washed with water, sodium bicarbonate solution, and again with water. The solution is then dried over sodium sulfate and concentrated to dryness in vacuo. Pure l2a-chloroallopregnane-l711,21-di0l-3,11,20-trione 21-acetate after recrystallization from acetone-hexane has the following properties: M.P. about 2l42l6; [(11 +4 (c. 0.83 in CHCl 2.93 5.74 5.82 ,u, 5.88 t Analysis.Calcd. for C H O Cl (438.92): C, 62.93; H, 7.11. Found: C, 63.25; H, 7.31.

Similarly 12a-fiuoro-allopregnane-3B,17a,21-triol-l1,20- dione 21-acetate can be oxidized to l2a-fluoro-allopregnane-17a,21-diol-3,l1,20-trione 2l-acetate (XXV).

' EXAMPLE 16 IZu-chloro-allopregnane-l 7a-0l-3,11,20-zri0ne (XXVI) 17 ml. of water. After ;-rernova l of ,the acetone in .vacuo the resulting mixture extracted with chloroform, the chloroform extract washed with water, dilute sodium bicarbonate and again with water, dried over sodium sulfate and :evaporated to. dryness in vacuo. The residue upon crystallization from alcohol furnishes pure 12at chloroallopregnan'e-17 ol-3,1 1,20-tr'ione (XXVI).

17 t-o1-'3,11,'20-trione '(XXVII).

EXAMPLE '17 1 20; "c lil r o 2 34b: dibr0ma -al'lopfe t nane "1704,21- di0l-3,1'1,2()-"tri'0n'e 21 -'acetate (XXVIII) To a solution of 200 mg. ,of .i1 -2u-chloroallopregnane- 17a,21-diol-3,l1,20-trione Zlac etate (XXIV) in 13 ml. of glacial acetic acid is added atroom temperature with stirring 3.35 'ml. of a solution "of bromine in glacial acetic'a'cid (4 5.4 'mgfimlz). To initiate reaction a few drops of 10% hydrogenibromide 'in acetic acid ar e added.

*Biorriination isc'omplete latter 3 hours. The mixture is EXAMPLE 1s 1'20t-c'hloro 2ouiodocortisone '21 -acetate 11) .A solution ,ofi90 mg. of the dibrom'ide-(XXVIII) prepared by the procedure of Example 17 and 240 mg. of

"sodiumiodide in m1. of acetone is refluxed for 18.5

hours. The reaction mixture is diluted with water and the acetone removed i'nvacuo. The resulting suspension is extracted'with chloroform and the chloroform solu- "tion washed'withwater containing atrace of sodium sulfite. Evaporation ;.of the sodium sulfate-dried chloroformYX f- 'act in yacuo leavesthe 2-iodide as a crystalline residuewhich after recrystallization 'from'aceton'e-hexane melts at about166- 167" '(dec.);

is; 24.0 m, $14,000)

frhe 'iedi de "is "used-in th1e're'ac'tion of E ample 19 without recrystallization.

Similarly, 12u-fluoro-2a,4a dibromo-allopregnane-l7a, 2l-diol-3,11 ,20-trione 21-acetate (XXIX), 12ct-Cl'll01'O-2oz, 4m-dibro'ino-allopreg'nane l7ot ol-3,11,20 trione (XXX), and 120: fluoro- 2a,4a-dibrorno-allopregnane-17u-ol-3,1 1, rzo-tion (XXXI) can be converted to IZa-flu ro-Za- {iodocortisone ll-acetate (XXXIII), l2a-chloro-2aaiodo- 17u-hydroxy-11-ketoprogesterone (XXXIV), and 12afiuoro 2oz iodo 17a hydroxy 11 keto-progesterone (XXXV), respectively.

EXAMPLE 19 12ot-chl0r0c0rtis0ne 21 -acetate (XXXVI) To a solution of 50 mg. of the 120t chloro-2a-iodide (XXXII) of Example 18 in 3 ml. of acetone is added under nitrogen 0.6 ml. of an aqueous chromous chloride solution (prepared from 5 g. of chromic chloride in 20 ml. of water). The mixture is allowed to remain at room temperature for minutes, after which time water and chloroform are added. The resulting chloroform extract is washed with water, dilute sodium bicarbonate and again with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residual material crystallizes readily and furnishes pure Hot-chlorocortisone acetate upon recrystallization from alcoho1,jM.P. about 185 mg, 230 my (e= 14,000) The material obtained in this fashion contains some chloroallopregn'ane-170;,2l-diol-3,11,20-trione 21-acetate as shown by the low extinction coefficient. It is therefore purified by chromatography on acid-washed alumina (l g.) in the following manner: the substance is dissolved in 3 ml. of benzene and 3 ml. of hexane, poured Anqlysis.-Calcd. for C H O' Cl (436.91): C, 63.22;

H, 6.69; Cl, 8.11. Found: C, 63.18; H, 6.84; CI, 8.06.

Similarly, 120t-fluoro-20t-iodocortisone 21-a'cetate, 12achloro-2a -iodo-1'7ot-hydroxy 1l-ketoprogesterone and 120:- fluoro-2u-iodo-l7ot hydroxy-l l-ketoprogesterone can be deiodinated to yield l2a-fluorocortisone 2l-acetate (XXV II), 120: ChlOl'O-170t-hY'dI'OXY-1 l-ketoprogesterone (XXXVIII) and l2m-fiuoro-l7a-hydroxy-ll-ketoprogesterone (XXXIX), respectively.

EXAMPLE 20 IZu-chlorocortz'sone (XLI V) To a solution of 50 mg. of '12u-chloroc-ortisone acetate (XXXVI) ;in '3 ml. of methanol is added under nitrogen 0.6 ml. of oxygen free 10% aqueous potassium carbonate. After '30 minutes at room temperature the sol'ut-ion'is neutralized with glacial acetic acid and diluted with 3 ml. of

Water. Crystallization ensued which becomes complete after removal of the methanol in vacuo. Thecrystals are collected on a filter, washed with water, dried and recrystallized from 95% alcohol.

Similarly, 12a-fluorocortisone 2l-acetate can be by- :drolyzed to 12a fiuorocortisone.

EXAMPLE 21 12u-chloro-A -pregnadiene-l 7a,21-di0l-3,]1,20-tri0ne -21-acetate (XL) A-solution of "500 mg. of "12a-chloro-2u,4a-dibrornoallopregnane-l7u,21-diol-3,11,20-trione (XXVIII) in 5 mrl. of collidine is refluxed for 45 minutes and the resulting mixture diluted with chloroform and dilute hydrochloric acid. The resultingchloroform extract is extracted with hydrochloric acid until free of collidine and finally with water. The sodium sulfate dried extract is -;evaporated in vacuo, dissolved in 2 ml. of chloroform and 8 ml. of "benzene and the resulting solution chromatographed 011-8 grams of sulfuric acid-washed alumina. The column is first eluted with benzene-chloroform 1:1 (400 ml.) to remove impurities, and then with chloroform (400 ml.). The latter solvent elutes .the desired l-dehydro-12a-ch1orocortisone acetate (XL), which is obtained in pure form by crystallization from 95 alcohol.

Similarly, 12a fiuoro-2a,4a-dibromo-allopregnane-17a, 21-diol-3,11,20-trione 21-acetate (XXIX), IZa-ChlOlO-Za, 4ot-dibromo-allopregnane 17 a-Ol-3,ll,20 trione (XXX) and 120t-fl11010-2oz,4ot dibromo-allo-pregnane-17a-0l-3,11, 20-trione (XXXI) can be converted to lZu-fillOlO- A -pregnadiene-17oa21 diol 3,11,20 trione 21-acetate (XLI), 12a-chloro-A -pregnadiene-1711-01-3,11,20 trione (XLII), and 12ot-fluoro-A -pregnadiene 17a-Ol-3,l1,20- trione (XLIII), respectively.

Compounds XL and XLI can then be hydrolyzed to the free 21-hydroxy steroid by the method of Example 20.

The following examples illustrate one of the processes for converting the 11-keto steroids to their llp-hydroxy derivatives.

EXAMPLE 22 A mixture of 200 mg. of 12a-chlorocortisone (XLIV), 4 ml. of ethylene glycol, 18 ml. of benzene and 15 mg. of p-toluenesulfonic acid monohydrate is refluxed for 5 hours with the aid of a Dean-Stark water separator. After cooling of the reaction mixture, dilute sodium bicarbonate solution is added and the layers are separated. The aqueous phase is extracted with chloroform, the organic phases combined, washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue representing 3,20-diethylene ketal of 12a-chlor0cortisone is used in the subsequent reaction of Example 23 without further purification.

EXAMPLE 23 3,20-diethylene ketal of I2a-chl0r0hydroc0rtisone (XL VI A solution of 200 mg. of the diketal (XLV) prepared in Example 22 and 100 mg. of potassium borohydride in 10 1 ml. of tetrahydrofuran and 5 ml. of water is allowed to react at room temperature for minutes and then at reflux for an additional 6 hours. After cooling, the mixture is concentrated in vacuo to remove the bulk of the tetrahydrofuran and the resulting suspension extracted with chloroform. The chloroform extract is washed with water, dried over sodium sulfate and the solvent removed in vacuo. Crystallization of the residue from acetonehexane yields the 3,20-diketal of 12a-chlorohydrocortisone (XLVI) in pure form.

EXAMPLE 24 I 12a-chlorohydrocortisone (XLIX) A solution of 100 mg. of 12ot-hydrocortisone-3,20-di-v ethylene ketal (XLVI) in 15 ml. of methanol and 1.5 ml.

extract is washed with dilute sodium bicarbonate and water, dried over sodium sulfate and evaporated to dryness in vacuo. The crystalline residue is recrystallized from 95% alcohol and furnishes the pure 12a-chlorohydrocortisone (XLIX).

EXAMPLE 25 M-pregnene-I 1,8,1218-0xid0-I 7a,21-di0l-3,20-di0ne (XL VII 20 The 115,12/8-oxide (XLVII) is acetylated with pyridineacetic anhydride to form A -pregnene-1lfi,12fl-oxido-17u, 21-diol-3,20-dione ZI-acetate (XLVIII) EXAMPLE 26 IZa-bromohydrocortisone acetate (L) To a solution of 100 mg. of A -pregnene-11fl,12;3-oxido- 17a,21-diol-3,20-dione 2l-acetate (XLVIII) in 5 ml. of dioxane is added at 0 0.3 ml. of 48% HBr. The mixture is allowed to remain at 0 for one hour and is then diluted with chloroform and water. The chloroform extract is washed with dilute sodium bicarbonate and water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue is crystallized carefully from alcohol.

EXAMPLE 27 12a-br0moc0rtisone acetate 12a-bromohydrocortisone acetate (L) is oxidized with chromic acid-sulfuric acid in acetone as described in Example 2 to yield 12a-bromocortisone acetate.

The invention may be variously otherwise embodied within the scope of the appended claims.

We claim:

1. A IZu-halo steroid of the general formula CHzY wherein at least one of the positions 1, 2 and 4, 5 is double-bonded, R is hydrogen, R is selected from the group consisting of hydroxy and acyloxy, and together R and R is selected from the group consisting of keto, ketal and semicarbazone; R" is hydrogen, R is hydroxy, and together R" and R is keto; X is a-halo; Y is selected from the group consisting of hydrogen, bromine, hydroxy and acyloxy, and Z is selected from the group consisting of keto, ketal and semicarbazone.

. 12a-halo-allopregnane-3/3,17a-diol-11,20-dione.

. 12a-halo-allopregnane-3 3,17a,2l-triol-l1,20-dione.

. l2a-halo-alloprcgnane-17a,21-diol-3,11,20-trione.

. 12a-halo-cortisone.

. 12a-chloro-cortisone.

1Zen-halo-A -pregnadiene-l7a-21-diol-3,1 1,20-trione. 12a chloro-A -pregnadiene-17a,21 diol-3,11,20- trione.

Archer June 15, 1954 Wettstein Feb. 19, 1957 

1. A 12A-HALO STEROID OF THE GENERAL FORMULA 